Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses

Abstract

A method for the treatment of a cutaneous, ocular, or mucosal pathological condition which is associated with immune response in a human or other mammal, that includes topical application of an effective amount of spiperone or a spiperone derivative or its pharmaceutically acceptable salt, in a pharmaceutically-acceptable diluent or carrier for topical application.

We claim: 
     
       1. A method for the treatment of a cutaneous, ocular, or mucosal pathology associated with an immune response in a human or other mammal comprises topical application of an effective amount of a compound selected from the group consisting of a quaternary salt of spiperone and a quaternary salt of a spiperone derivative of the formula: ##STR5## wherein R 1  =H; alkyl, Y--CH 2  (CH 2 ) n  -- or Ar 1 , R 2  =H or C 1  to C 20  alkyl;   R 3  =H; alkyl, CN(CH 2 ) 2  --; X--(CH 2 ) n  --; X--(CH 2 ) n  CO--; NH 2  C(NH)NHC(NH)(aryl)(CH 2 ) n  --; or X-(aryl)-(CH 2 ) n  --;   R 4  =H, C 6  H 5  CH(CH 2  CH 3 )CH 2  --, C 6  H 5  CH(CH 3 )(CH 2 ) 2  --, C 6  H 5  CH 2  CH(CH 3 )CH 2  --, C 6  H 5  CH 2  CH 2  CH(CH 3 )--, C 6  H 5  CH(CH 3 )(CH 2 ) 3  --, (2, 3, or 4)-(alkyl)-C 6  H 4  CH(CH 3 )(CH 2 ) 3  --, (2, 3, or 4)-(alkyloxy)-C 6  H 4  CH(CH 3 )(CH 2 ) 3 , C 6  H 5  CH(OCH 3 )(CH 2 ) 2  --, ##STR6##  C 6  H 5  CO(CH 2 ) 3 , C 6  H 5  CO(CH 2 ) 4  --, (2, 3, or 4)-(alkyl)-C 6  H 4  CO(CH 2 ) 3  --, (2, 3, or 4)-(alkyl-oxy)-C 6  H 4  CO(CH 2 ) 3  --, (2, 3, or 4)-X--C 6  H 4  -alkyl-, (2, 3, or 4)-X--C 6  H 4  CO(CH 2 ) n  --, 2-thienyl-CO-(CH 2 ) 3  --, ##STR7##  (2, 3, or 4)-X--C 6  H 4  C(CH 3 )CH(CH 2 ) 2  --, where the conformation about the double bond is cis or trans,    (2, 3, or 4)-X--C 6  H 4  C(CH 3 )CHCH 2  --, where the conformation about the double bond is cis or trans,    (2, 3, or 4)-X--C 6  H 4  COCH═CHCH 2  --, Y--CH 2  (CH 2 ) n  --, Ar 1  --(CH 2 ) n  --, C 1  to C 20  alkyl, X--(CH 2 ) n  CO--, or X--(CH 2 ) n  --;   n=1 to 6;   p is 1 to 20;   X=is independently F, Cl, Br, I, OCH 3 , SO 3   - , NH 2 , H, --OH, --COOH, --COOR, wherein R is alkyl or benzyl, --SO 3  H, --CN, --NHSO 3  H, --NO 2 , or --SO 2  NH 2  ;   Y=H, F, Cl, Br, I, --SO 3 , --PO 4   = , --OH, --SH, --SCH 3 , --CH 3  SO 2   - , --NH 2 , or --CO 2   -  ; and   Ar 1  is, independently, aryl, (2, 3, or 4-X--C 6  H 4  --), (2, 3, or 4)-(CH 2  X)C 6  H 4  --, (2, 3, or 4)-(CX 3 )C 6  H 4  --, (2, 3, or 4)-(CHX 2 )C 6  H 4  --, 2-thienyl, or (2, 3, or 4)-X--C 6  H 4  CH 2  --;   or its pharmaceutically acceptable salt optionally in a pharmaceutical carrier.   
     
     
       2. The method of claim 1, wherein the alkyl group is selected from the group consisting of cyclohexyl, (CH 3 ) 2  CH--, (CH 3 ) 2  CHCH 2  --, CH 3  CH 2  CH(CH 3 )--, (CH 3 ) 3  C--, (CH 3 ) 2  CH--, and CH 3  (CH 2 ) n  --. 
     
     
       3. The method of claim 1, wherein the Ar 1  group is selected from the group consisting of C 6  H 5  --, (2, 3, or 4)-(OCH 3 )C 6  H 4  - and (2, 3, or 4)-(CH 3 )C 6  H 4  --; 2-X--C 6  H 4  --, 3-X--C 6  H 4  --, and 4-X--C 6  H 4  --. 
     
     
       4. The method of claim 1, wherein (2, 3, or 4)-X--C 6  H 4  -alkyl- is selected from the group consisting of (2, 3, or 4)-X--C 6  H 4  CH(CH 2  CH 3 )CH 2  --, (2, 3, or 4)-X--C 6  H 4  CH(CH 3 )(CH 2 )--, (2, 3, or 4)-X--C 6  H 4  CH(CH 3 )(CH 2 ) 2  --, and (2, 3, or 4)-X--C 6  H 4  --CH(CH 3 )(CH 2 ) 3  --. 
     
     
       5. The method of claim 1, wherein the quaternary ammonium salt is of the formula .tbd.N(R) +  Z - , wherein R is alkyl or benzyl, and Z is a counteranion. 
     
     
       6. The method of claim 5, wherein the counteranion is selected from the group consisting of chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, and carboxylate. 
     
     
       7. The method of claim 6, wherein the carboxylate is selected from the group consisting of benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate. 
     
     
       8. The method of claim 1 wherein the mammal is a human. 
     
     
       9. The method of claim 1, wherein the pathology associated with an immune response is selected from the group consisting of contact dermatitis, atopic dermatitis, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, eczematous dermatitis, drug eruptions, lichen planus, psoriasis, alopecia areata, cutaneous lupus erythematosus, scleroderma, asthma, allergic asthma, ulcerative colitis, Crohn's disease, allergic reactions secondary to arthropod bite reactions, aphthous ulcers, conjunctivitis, iritis, keratoconjunctivitis, vaginitis, and proctitis. 
     
     
       10. The method of claim 1, wherein the carrier is a mouthwash. 
     
     
       11. The method of claim 1, wherein the carrier is a spit and swish solution. 
     
     
       12. The method of claim 1 wherein the compound in combination with an ophthalmic carrier is topically applied to the eye. 
     
     
       13. The method of claim 1, wherein the compound is applied cutaneously. 
     
     
       14. The method of claim 1, wherein the compound is applied to mucosal membranes. 
     
     
       15. The method of claim 1, wherein the daily dose of compound is between 0.1 milligrams and 120 grams. 
     
     
       16. The method of claim 1, wherein the compound is applied in a concentration between 0.001% and 50%. 
     
     
       17. The method of claim 1 wherein the compound is administered in a time release formulation. 
     
     
       18. The method of claim 1, wherein the compound is administered via a retention enema. 
     
     
       19. The method of claim 1, wherein the compound is administered in combination with another compound selected from the group consisting of antivirals, antifungals, antibiotics, anti-inflammatories, and other immunosuppressants, bronchodilators or other therapeutic agents for asthma. 
     
     
       20. The method of claim 1, wherein the salt is prepared by combining spiperone or a spiperone derivative with a compound selected from the group consisting of: methyl chloride, methyl bromide, methyl iodide, methyl sulfate, methyl benzene-sulfonate, methyl p-toluenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-butyl bromide, isobutyl bromide, sec-butyl bromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, benzyl bromide, and ethyl sulfate.